DESCRIPTION : Drug addiction is a disease characterized by compulsive drug or substance use despite adverse health, economic, or social consequences. It is thought that mechanisms that guide goal-directed behaviors to seek rewards and avoid danger also drive goal-directed behavior for drugs of abuse (1,2). Thus, defining the neural circuitry important in processing rewarding and aversive stimuli will be necessary to better understand drug addiction, and hopefully lead to the investigation of novel treatments and therapeutic targets. The lateral habenula (LHb) to the ventral tegmental area (VTA) neural circuit is an intriguing novel circuit that is thought to process aversive stimuli and negative reward information (15,16). The goals of this proposal are to provide a thorough investigation of the LHb-VTA pathway after exposure to aversive stimuli as well as how specific manipulations of this pathway affect aversive-like behaviors. To complete the first goal, I will use ex vivo electrophysiology paired with optogenetics to investigate changes in excitatory strength in the LHb-VTA pathway following exposure to aversive stimuli. To complete the second goal, I will utilize in vivo optogenetics to determine if excitation of the LHb-VTA pathway is aversive and if mice will learn to operantly respond to avoid activation of this pathway. Furthermore, I will inhibit this pathway to investigat whether this pathway is necessary to learn associations between a cue and an aversive stimulus. Taken together, this proposal will provide a thorough and novel characterization of the LHb-VTA neural circuit after exposure to aversive stimuli, and investigate how specific manipulations of this pathway contributes to aversive-like behavior. PUBLIC HEALTH RELEVANCE: Drug addiction is a disease characterized by compulsive drug or substance use despite adverse health, economic, or social consequences. The research generated in this proposal will investigate a discrete neural circuit thought to be critical in processing aversive or non-rewarding stimuli, and is thought to become aberrantly engaged during drug addiction and other neuropsychiatric disorders such as anxiety disorders. These data will shed light on the neurobiological mechanisms underlying aversive processing, and may lead to the development of potential therapeutics to treat drug addiction.